1. Field of the Invention
The present invention relates to dry powder formulations suitable for the inhalatory administration by means of a dry powder inhaler. The present invention also relates to processes for the preparation of such a formulation, and to the use of such a formulation for the prevention and/or treatment of an inflammatory or obstructive airways disease such as asthma and COPD.
2. Discussion of the Background
Airway obstruction characterizes a number of severe respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include edema of airway walls, increased mucous production and inflammation.
Drugs for treating respiratory diseases such as asthma and COPD are currently administered through inhalation. One of the advantages of the inhalatory route over the systemic one is the possibility of delivering the drug directly at site of action, avoiding any systemic side-effects, thus providing a more rapid clinical response and a higher therapeutic ratio.
An important class of therapeutic agents which are under investigation in view of its anti-inflammatory effects for the treatment of inflammatory respiratory diseases is represented by the inhibitors of the phosphodiesterase enzymes (PDEs), in particular inhibitors of the phosphodiesterase type 4 (hereinafter referred to as PDE4).
Various compounds acting as PDE4 inhibitors have been disclosed. However, the usefulness of several PDE4 inhibitors of the first-generation such as rolipram and piclamilast has been limited because of their undesirable side effects such as nausea, gastric acid secretion and emesis due to their action on PDE4 in the central nervous system and due to the action on PDE4 in parietal cells in the gut.
The cause of said side effects has been widely investigated. It has been found that PDE4 exists in two distinct forms representing different conformations, that were designated as high affinity rolipram binding site or HPDE4, especially present in the central nervous system and in parietal cells, and low affinity rolipram binding site or LPDE4 (see Jacobitz, S et al., Mol. Pharmacol., 1996, 50, 891-899, which is incorporated herein by reference in its entirety), which is found in the immune and inflammatory cells. While both forms appear to exhibit catalytic activity, they differ with respect to their sensitivity to inhibitors. In particular, compounds with higher affinity for LPDE4 appear less prone to induce side-effects such as nausea, emesis, and increased gastric secretion.
Thus, it would be advantageous to provide selective inhibitors of the LPDE4 form, therapeutically effective upon administration by inhalation.
Compounds with selective LPDE4 inhibition activity are disclosed in WO 2009/018909, which is incorporated herein by reference in its entirety. Additional PDE4 inhibitors having high potency are an object of the co-pending International Patent Application No. PCT/EP2010/000676 (which is incorporated herein by reference in its entirety), wherein it has been surprisingly found that the presence of sulphonamido substituents on the benzoate residue markedly improves the potency and that the (−) enantiomers are more potent than the corresponding (+) enantiomers and racemates. Moreover, it has been found that they could act in a synergistic way in combination with long-acting β2-agonists.
Therefore these compounds may provide significant therapeutic benefit in the treatment of respiratory diseases such as asthma and COPD, when administered by inhalation.
Thus, there remains a need for formulations for delivering such compounds by inhalation.